請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/80362完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李明學(Ming-Shyue Lee) | |
| dc.contributor.author | Hsin-Fang Tu | en |
| dc.contributor.author | 涂馨方 | zh_TW |
| dc.date.accessioned | 2022-11-24T03:05:10Z | - |
| dc.date.available | 2021-07-07 | |
| dc.date.available | 2022-11-24T03:05:10Z | - |
| dc.date.copyright | 2021-07-07 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-06-23 | |
| dc.identifier.citation | 1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65(2):87-108 doi 10.3322/caac.21262. 2. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83(5):584-94 doi 10.4065/83.5.584. 3. Oxnard GR, Binder A, Janne PA. New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol 2013;31(8):1097-104 doi 10.1200/JCO.2012.42.9829. 4. Tao RH, Maruyama IN. All EGF(ErbB) receptors have preformed homo- and heterodimeric structures in living cells. J Cell Sci 2008;121(Pt 19):3207-17 doi 10.1242/jcs.033399. 5. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000;19(56):6550-65 doi 10.1038/sj.onc.1204082. 6. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361(10):947-57 doi 10.1056/NEJMoa0810699. 7. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12(8):735-42 doi 10.1016/S1470-2045(11)70184-X. 8. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27(34):4702-11 doi 10.1038/onc.2008.109. 9. Matsuo N, Azuma K, Sakai K, Hattori S, Kawahara A, Ishii H, et al. Association of EGFR Exon 19 Deletion and EGFR-TKI Treatment Duration with Frequency of T790M Mutation in EGFR-Mutant Lung Cancer Patients. Sci Rep 2016;6:36458 doi 10.1038/srep36458. 10. Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 2010;28(2):357-60 doi 10.1200/JCO.2009.24.7049. 11. Mahoney KM, Rennert PD, Freeman GJJNrDd. Combination cancer immunotherapy and new immunomodulatory targets. 2015;14(8):561-84. 12. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1(5):405-13. 13. Krummel MF, Allison JP. Pillars article: CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. The journal of experimental medicine. 1995. 182: 459-465. J Immunol 2011;187(7):3459-65. 14. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271(5256):1734-6. 15. Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1994;1(9):793-801 doi 10.1016/s1074-7613(94)80021-9. 16. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991;174(3):561-9 doi 10.1084/jem.174.3.561. 17. van der Merwe PA, Bodian DL, Daenke S, Linsley P, Davis SJ. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med 1997;185(3):393-403 doi 10.1084/jem.185.3.393. 18. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711-23 doi 10.1056/NEJMoa1003466. 19. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996;8(5):765-72 doi 10.1093/intimm/8.5.765. 20. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 2012;209(6):1201-17 doi 10.1084/jem.20112741. 21. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455-65 doi 10.1056/NEJMoa1200694. 22. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015;373(17):1627-39 doi 10.1056/NEJMoa1507643. 23. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015;373(2):123-35 doi 10.1056/NEJMoa1504627. 24. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372(21):2018-28 doi 10.1056/NEJMoa1501824. 25. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515(7528):563-7 doi 10.1038/nature14011. 26. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387(10027):1540-50 doi 10.1016/S0140-6736(15)01281-7. 27. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375(19):1823-33 doi 10.1056/NEJMoa1606774. 28. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 2018;378(24):2288-301 doi 10.1056/NEJMoa1716948. 29. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378(22):2078-92 doi 10.1056/NEJMoa1801005. 30. Hallqvist A, Rohlin A, Raghavan S. Immune checkpoint blockade and biomarkers of clinical response in non-small cell lung cancer. Scand J Immunol 2020;92(6):e12980 doi 10.1111/sji.12980. 31. Gettinger SN, Horn L, Gandhi L, Spigel DR, Antonia SJ, Rizvi NA, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2015;33(18):2004-12 doi 10.1200/JCO.2014.58.3708. 32. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016;387(10030):1837-46 doi 10.1016/S0140-6736(16)00587-0. 33. Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389(10066):255-65 doi 10.1016/S0140-6736(16)32517-X. 34. Jin R, Zhao J, Xia L, Li Q, Li W, Peng L, et al. Application of immune checkpoint inhibitors in EGFR-mutant non-small-cell lung cancer: from bed to bench. Ther Adv Med Oncol 2020;12:1758835920930333 doi 10.1177/1758835920930333. 35. Berghoff AS, Bellosillo B, Caux C, de Langen A, Mazieres J, Normanno N, et al. Immune checkpoint inhibitor treatment in patients with oncogene- addicted non-small cell lung cancer (NSCLC): summary of a multidisciplinary round-table discussion. ESMO Open 2019;4(3):e000498 doi 10.1136/esmoopen-2019-000498. 36. Huang Q, Zhang H, Hai J, Socinski MA, Lim E, Chen H, et al. Impact of PD-L1 expression, driver mutations and clinical characteristics on survival after anti-PD-1/PD-L1 immunotherapy versus chemotherapy in non-small-cell lung cancer: A meta-analysis of randomized trials. Oncoimmunology 2018;7(12):e1396403 doi 10.1080/2162402X.2017.1396403. 37. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015;348(6230):124-8 doi 10.1126/science.aaa1348. 38. Mazzaschi G, Madeddu D, Falco A, Bocchialini G, Goldoni M, Sogni F, et al. Low PD-1 Expression in Cytotoxic CD8(+) Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value. Clin Cancer Res 2018;24(2):407-19 doi 10.1158/1078-0432.CCR-17-2156. 39. Dong ZY, Zhang JT, Liu SY, Su J, Zhang C, Xie Z, et al. EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer. Oncoimmunology 2017;6(11):e1356145 doi 10.1080/2162402X.2017.1356145. 40. Haratani K, Hayashi H, Tanaka T, Kaneda H, Togashi Y, Sakai K, et al. Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment. Ann Oncol 2017;28(7):1532-9 doi 10.1093/annonc/mdx183. 41. Toki MI, Mani N, Smithy JW, Liu Y, Altan M, Wasserman B, et al. Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations. J Thorac Oncol 2018;13(12):1884-96 doi 10.1016/j.jtho.2018.09.012. 42. Zhang N, Zeng Y, Du W, Zhu J, Shen D, Liu Z, et al. The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer. Int J Oncol 2016;49(4):1360-8 doi 10.3892/ijo.2016.3632. 43. Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. 2013;3(12):1355-63. 44. Aoun F, Kourie HR, Sideris S, Roumeguere T, van Velthoven R, Gil T. Checkpoint inhibitors in bladder and renal cancers: results and perspectives. Immunotherapy 2015;7(12):1259-71 doi 10.2217/imt.15.91. 45. Chen N, Fang W, Zhan J, Hong S, Tang Y, Kang S, et al. Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation. J Thorac Oncol 2015;10(6):910-23 doi 10.1097/JTO.0000000000000500. 46. D'Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer 2015;112(1):95-102 doi 10.1038/bjc.2014.555. 47. Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, Tanizaki J, et al. Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer. Clin Cancer Res 2015;21(17):4014-21 doi 10.1158/1078-0432.CCR-15-0016. 48. Chen N, Fang W, Zhan J, Hong S, Tang Y, Kang S, et al. Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. 2015;10(6):910-23. 49. Hong S, Chen N, Fang W, Zhan J, Liu Q, Kang S, et al. Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients. Oncoimmunology 2016;5(3):e1094598 doi 10.1080/2162402X.2015.1094598. 50. Ahn MJ, Sun JM, Lee SH, Ahn JS, Park K. EGFR TKI combination with immunotherapy in non-small cell lung cancer. Expert Opin Drug Saf 2017;16(4):465-9 doi 10.1080/14740338.2017.1300656. 51. Gettinger S, Hellmann MD, Chow LQM, Borghaei H, Antonia S, Brahmer JR, et al. Nivolumab Plus Erlotinib in Patients With EGFR-Mutant Advanced NSCLC. J Thorac Oncol 2018;13(9):1363-72 doi 10.1016/j.jtho.2018.05.015. 52. Yang JC, Gadgeel SM, Sequist LV, Wu CL, Papadimitrakopoulou VA, Su WC, et al. Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced NSCLC With Sensitizing EGFR Mutation. J Thorac Oncol 2019;14(3):553-9 doi 10.1016/j.jtho.2018.11.028. 53. Chih-Hsin Yang J, Shepherd FA, Kim DW, Lee GW, Lee JS, Chang GC, et al. Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC following Previous EGFR TKI Therapy: CAURAL Brief Report. J Thorac Oncol 2019;14(5):933-9 doi 10.1016/j.jtho.2019.02.001. 54. Swaika A, Hammond WA, Joseph RW. Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol Immunol 2015;67(2 Pt A):4-17 doi 10.1016/j.molimm.2015.02.009. 55. Johnson DB, Rioth MJ, Horn L. Immune checkpoint inhibitors in NSCLC. Curr Treat Options Oncol 2014;15(4):658-69 doi 10.1007/s11864-014-0305-5. 56. Ott PA, Adams S. Small-molecule protein kinase inhibitors and their effects on the immune system: implications for cancer treatment. Immunotherapy 2011;3(2):213-27 doi 10.2217/imt.10.99. 57. Luo Q, Gu Y, Zheng W, Wu X, Gong F, Gu L, et al. Erlotinib inhibits T-cell-mediated immune response via down-regulation of the c-Raf/ERK cascade and Akt signaling pathway. Toxicol Appl Pharmacol 2011;251(2):130-6 doi 10.1016/j.taap.2010.12.011. 58. Wehrstedt S, Kubis J, Zimmermann A, Bruns H, Mayer D, Grieshober M, et al. The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T-cell function. Eur J Immunol 2018;48(11):1892-903 doi 10.1002/eji.201847656. 59. DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: New estimates of R D costs. J Health Econ 2016;47:20-33 doi 10.1016/j.jhealeco.2016.01.012. 60. Sertkaya A, Wong HH, Jessup A, Beleche T. Key cost drivers of pharmaceutical clinical trials in the United States. Clin Trials 2016;13(2):117-26 doi 10.1177/1740774515625964. 61. Wong CH, Siah KW, Lo AW. Corrigendum: Estimation of clinical trial success rates and related parameters. Biostatistics 2019;20(2):366 doi 10.1093/biostatistics/kxy072. 62. Giuliano CJ, Lin A, Smith JC, Palladino AC, Sheltzer JM. MELK expression correlates with tumor mitotic activity but is not required for cancer growth. Elife 2018;7 doi 10.7554/eLife.32838. 63. Yu CH, Chou CC, Tu HF, Huang WC, Ho YY, Khoo KH, et al. Antibody-assisted target identification reveals afatinib, an EGFR covalent inhibitor, down-regulating ribonucleotide reductase. Oncotarget 2018;9(30):21512-29 doi 10.18632/oncotarget.25177. 64. Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med 2019;11(509) doi 10.1126/scitranslmed.aaw8412. 65. Mestres J, Gregori-Puigjane E, Valverde S, Sole RV. Data completeness--the Achilles heel of drug-target networks. Nat Biotechnol 2008;26(9):983-4 doi 10.1038/nbt0908-983. 66. Brown E. Pyrimdines, ring nitrogen and key biomolecules: the biochemistry of N-heterocycles. Springer; 1998. 67. Swyryd EA, Seaver SS, Stark GR. N-(phosphonacetyl)-L-aspartate, a potent transition state analog inhibitor of aspartate transcarbamylase, blocks proliferation of mammalian cells in culture. J Biol Chem 1974;249(21):6945-50. 68. Aoki T, Weber G. Carbamoyl phosphate synthetase (glutamine-hydrolyzing): increased activity in cancer cells. Science 1981;212(4493):463-5 doi 10.1126/science.7209543. 69. Brown KK, Spinelli JB, Asara JM, Toker AJCd. Adaptive reprogramming of de novo pyrimidine synthesis is a metabolic vulnerability in triple-negative breast cancer. 2017;7(4):391-9. 70. Li L, Ng SR, Colon CI, Drapkin BJ, Hsu PP, Li Z, et al. Identification of DHODH as a therapeutic target in small cell lung cancer. Sci Transl Med 2019;11(517) doi 10.1126/scitranslmed.aaw7852. 71. Brown KK, Spinelli JB, Asara JM, Toker A. Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer. Cancer Discov 2017;7(4):391-9 doi 10.1158/2159-8290.CD-16-0611. 72. Quemeneur L, Gerland LM, Flacher M, Ffrench M, Revillard JP, Genestier L. Differential control of cell cycle, proliferation, and survival of primary T lymphocytes by purine and pyrimidine nucleotides. J Immunol 2003;170(10):4986-95 doi 10.4049/jimmunol.170.10.4986. 73. Christopherson RI, Lyons SD. Potent inhibitors of de novo pyrimidine and purine biosynthesis as chemotherapeutic agents. Med Res Rev 1990;10(4):505-48. 74. Fairbanks LD, Bofill M, Ruckemann K, Simmonds HA. Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans. Disproportionate expansion of pyrimidine pools and contrasting effects of de novo synthesis inhibitors. The Journal of biological chemistry 1995;270(50):29682-9. 75. Marijnen YM, de Korte D, Haverkort WA, den Breejen EJ, van Gennip AH, Roos D. Studies on the incorporation of precursors into purine and pyrimidine nucleotides via 'de novo' and 'salvage' pathways in normal lymphocytes and lymphoblastic cell-line cells. Biochim Biophys Acta 1989;1012(2):148-55 doi 10.1016/0167-4889(89)90088-8. 76. Fairbanks LD, Bofill M, Ruckemann K, Simmonds HAJJoBC. Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans: disproportionate expansion of pyrimidine pools and contrasting effects of de novo synthesis inhibitors. 1995;270(50):29682-9. 77. Cope AP, Schulze-Koops H, Aringer M. The central role of T cells in rheumatoid arthritis. Clin Exp Rheumatol 2007;25(5 Suppl 46):S4-11. 78. Ruckemann K, Fairbanks LD, Carrey EA, Hawrylowicz CM, Richards DF, Kirschbaum B, et al. Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans. J Biol Chem 1998;273(34):21682-91 doi 10.1074/jbc.273.34.21682. 79. Breedveld FC, Dayer JM. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis 2000;59(11):841-9 doi 10.1136/ard.59.11.841. 80. Cherwinski HM, McCarley D, Schatzman R, Devens B, Ransom JT. The immunosuppressant leflunomide inhibits lymphocyte progression through cell cycle by a novel mechanism. J Pharmacol Exp Ther 1995;272(1):460-8. 81. Josephson MA, Javaid B, Kadambi PV, Meehan SM, Williams JW. Leflunomide in solid organ transplantation and polyoma virus infection. Adv Exp Med Biol 2006;577:255-65 doi 10.1007/0-387-32957-9_18. 82. Forrest TL, Ware RE, Howard T, Jaffee BD, Denning SM. Novel mechanisms of brequinar sodium immunosuppression on T cell activation. Transplantation 1994;58(8):920-6 doi 10.1097/00007890-199410270-00011. 83. Coleman PF, Suttle DP, Stark GR. Purification from hamster cells of the multifunctional protein that initiates de novo synthesis of pyrimidine nucleotides. J Biol Chem 1977;252(18):6379-85. 84. Evans DR, Guy HI. Mammalian pyrimidine biosynthesis: fresh insights into an ancient pathway. J Biol Chem 2004;279(32):33035-8 doi 10.1074/jbc.R400007200. 85. Jones ME. Pyrimidine nucleotide biosynthesis in animals: genes, enzymes, and regulation of UMP biosynthesis. Annu Rev Biochem 1980;49:253-79 doi 10.1146/annurev.bi.49.070180.001345. 86. Graves LM, Guy HI, Kozlowski P, Huang M, Lazarowski E, Pope RM, et al. Regulation of carbamoyl phosphate synthetase by MAP kinase. Nature 2000;403(6767):328-32 doi 10.1038/35002111. 87. Del Cano-Ochoa F, Ramon-Maiques S. The multienzymatic protein CAD leading the de novo biosynthesis of pyrimidines localizes exclusively in the cytoplasm and does not translocate to the nucleus. Nucleosides Nucleotides Nucleic Acids 2020;39(10-12):1320-34 doi 10.1080/15257770.2019.1706743. 88. Ruiz-Ramos A, Velazquez-Campoy A, Grande-Garcia A, Moreno-Morcillo M, Ramon-Maiques S. Structure and Functional Characterization of Human Aspartate Transcarbamoylase, the Target of the Anti-tumoral Drug PALA. Structure 2016;24(7):1081-94 doi 10.1016/j.str.2016.05.001. 89. Lallous N, Grande-Garcia A, Molina R, Ramon-Maiques S. Expression, purification, crystallization and preliminary X-ray diffraction analysis of the dihydroorotase domain of human CAD. Acta Crystallogr Sect F Struct Biol Cryst Commun 2012;68(Pt 11):1341-5 doi 10.1107/S1744309112038857. 90. Carrey EA, Campbell DG, Hardie DG. Phosphorylation and activation of hamster carbamyl phosphate synthetase II by cAMP-dependent protein kinase. A novel mechanism for regulation of pyrimidine nucleotide biosynthesis. EMBO J 1985;4(13B):3735-42. 91. Sigoillot FD, Berkowski JA, Sigoillot SM, Kotsis DH, Guy HI. Cell cycle-dependent regulation of pyrimidine biosynthesis. J Biol Chem 2003;278(5):3403-9 doi 10.1074/jbc.M211078200. 92. Ng BG, Wolfe LA, Ichikawa M, Markello T, He M, Tifft CJ, et al. Biallelic mutations in CAD, impair de novo pyrimidine biosynthesis and decrease glycosylation precursors. Hum Mol Genet 2015;24(11):3050-7 doi 10.1093/hmg/ddv057. 93. Lohmann K, Masuho I, Patil DN, Baumann H, Hebert E, Steinrucke S, et al. Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans. Hum Mol Genet 2017;26(6):1078-86 doi 10.1093/hmg/ddx018. 94. Renz JF, Lin Z, de Roos M, Dalal AA, Ascher NL. SCID mouse as a model for transplantation studies. J Surg Res 1996;65(1):34-41 doi 10.1006/jsre.1996.0340. 95. Bertram JS, Janik P. Establishment of a cloned line of Lewis Lung Carcinoma cells adapted to cell culture. Cancer Lett 1980;11(1):63-73 doi 10.1016/0304-3835(80)90130-5. 96. Sharma S, Stolina M, Lin Y, Gardner B, Miller PW, Kronenberg M, et al. T cell-derived IL-10 promotes lung cancer growth by suppressing both T cell and APC function. J Immunol 1999;163(9):5020-8. 97. Roose JP, Diehn M, Tomlinson MG, Lin J, Alizadeh AA, Botstein D, et al. T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression. PLoS Biol 2003;1(2):E53 doi 10.1371/journal.pbio.0000053. 98. Lyons GE, Moore T, Brasic N, Li M, Roszkowski JJ, Nishimura MI. Influence of human CD8 on antigen recognition by T-cell receptor-transduced cells. Cancer Res 2006;66(23):11455-61 doi 10.1158/0008-5472.CAN-06-2379. 99. Panda SK, Ravindran B. Isolation of Human PBMCs. Bio-protocol 2013;3(3):e323 doi 10.21769/BioProtoc.323. 100. Panda SK, Kumar S, Tupperwar NC, Vaidya T, George A, Rath S, et al. Chitohexaose activates macrophages by alternate pathway through TLR4 and blocks endotoxemia. PLoS Pathog 2012;8(5):e1002717 doi 10.1371/journal.ppat.1002717. 101. Wu SR, Cheng TS, Chen WC, Shyu HY, Ko CJ, Huang HP, et al. Matriptase is involved in ErbB-2-induced prostate cancer cell invasion. Am J Pathol 2010;177(6):3145-58 doi 10.2353/ajpath.2010.100228. 102. Carrey EA. Nucleotide ligands protect the inter-domain regions of the multifunctional polypeptide CAD against limited proteolysis, and also stabilize the thermolabile part-reactions of the carbamoyl-phosphate synthase II domains within the CAD polypeptide. Biochem J 1986;236(2):327-35 doi 10.1042/bj2360327. 103. Tan YS, Lei YL. Isolation of Tumor-Infiltrating Lymphocytes by Ficoll-Paque Density Gradient Centrifugation. Methods Mol Biol 2019;1960:93-9 doi 10.1007/978-1-4939-9167-9_8. 104. Han A, Glanville J, Hansmann L, Davis MM. Linking T-cell receptor sequence to functional phenotype at the single-cell level. Nat Biotechnol 2014;32(7):684-92 doi 10.1038/nbt.2938. 105. Wang C, Sanders CM, Yang Q, Schroeder HW, Jr., Wang E, Babrzadeh F, et al. High throughput sequencing reveals a complex pattern of dynamic interrelationships among human T cell subsets. Proc Natl Acad Sci U S A 2010;107(4):1518-23 doi 10.1073/pnas.0913939107. 106. Oakes T, Heather JM, Best K, Byng-Maddick R, Husovsky C, Ismail M, et al. Quantitative Characterization of the T Cell Receptor Repertoire of Naive and Memory Subsets Using an Integrated Experimental and Computational Pipeline Which Is Robust, Economical, and Versatile. Front Immunol 2017;8:1267 doi 10.3389/fimmu.2017.01267. 107. Shugay M, Britanova OV, Merzlyak EM, Turchaninova MA, Mamedov IZ, Tuganbaev TR, et al. Towards error-free profiling of immune repertoires. Nat Methods 2014;11(6):653-5 doi 10.1038/nmeth.2960. 108. Shugay M, Bagaev DV, Turchaninova MA, Bolotin DA, Britanova OV, Putintseva EV, et al. VDJtools: Unifying Post-analysis of T Cell Receptor Repertoires. PLoS Comput Biol 2015;11(11):e1004503 doi 10.1371/journal.pcbi.1004503. 109. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31(27):3327-34 doi 10.1200/JCO.2012.44.2806. 110. Wind S, Schnell D, Ebner T, Freiwald M, Stopfer P. Clinical Pharmacokinetics and Pharmacodynamics of Afatinib. Clin Pharmacokinet 2017;56(3):235-50 doi 10.1007/s40262-016-0440-1. 111. Nakao K, Kobuchi S, Marutani S, Iwazaki A, Tamiya A, Isa S, et al. Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer. Sci Rep 2019;9(1):18202 doi 10.1038/s41598-019-54804-9. 112. Allen CM, Jr., Jones ME. Decomposition of Carbamylphosphate in Aqueous Solutions. Biochemistry 1964;3:1238-47 doi 10.1021/bi00897a010. 113. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 2008;14(16):5220-7 doi 10.1158/1078-0432.CCR-08-0133. 114. Brambilla E, Le Teuff G, Marguet S, Lantuejoul S, Dunant A, Graziano S, et al. Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer. J Clin Oncol 2016;34(11):1223-30 doi 10.1200/JCO.2015.63.0970. 115. Geng Y, Shao Y, He W, Hu W, Xu Y, Chen J, et al. Prognostic Role of Tumor-Infiltrating Lymphocytes in Lung Cancer: a Meta-Analysis. Cell Physiol Biochem 2015;37(4):1560-71 doi 10.1159/000438523. 116. Kawai O, Ishii G, Kubota K, Murata Y, Naito Y, Mizuno T, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer 2008;113(6):1387-95 doi 10.1002/cncr.23712. 117. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014;124(2):687-95 doi 10.1172/JCI67313. 118. Zippelius A, Schreiner J, Herzig P, Muller P. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol Res 2015;3(3):236-44 doi 10.1158/2326-6066.CIR-14-0226. 119. Ngiow SF, Young A, Jacquelot N, Yamazaki T, Enot D, Zitvogel L, et al. A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1. Cancer Res 2015;75(18):3800-11 doi 10.1158/0008-5472.CAN-15-1082. 120. Bossennec M, Di Roio A, Caux C, Ménétrier-Caux CJO. MDR1 in immunity: friend or foe? 2018;7(12):e1499388. 121. Zhang J-C, Xie F, Yu X-H, Deng Z-Y, Wang Y, Liang P, et al. Expression levels of P-glycoprotein in peripheral blood CD8+ T lymphocytes from HIV-1-infected patients on antiretroviral therapy. 2014;33(2):431-40. 122. De Boer RJ, Mohri H, Ho DD, Perelson AS. Turnover rates of B cells, T cells, and NK cells in simian immunodeficiency virus-infected and uninfected rhesus macaques. J Immunol 2003;170(5):2479-87 doi 10.4049/jimmunol.170.5.2479. 123. Song P, Zhang J, Shang C, Zhang L. Real-world evidenceand clinical observations of the treatment of advanced non-small cell lung cancer with PD-1/PD-L1 inhibitors. Sci Rep 2019;9(1):4278 doi 10.1038/s41598-019-40748-7. 124. Taniguchi Y, Yamamoto M, Ikushima H, Ohara S, Takeshima H, Sakatani T, et al. Successful Treatment of Afatinib-Refractory Non-Small Cell Lung Cancer with Uncommon Complex EGFR Mutations Using Pembrolizumab: A Case Report. Case Rep Oncol 2019;12(2):564-7 doi 10.1159/000501848. 125. Isomoto K, Haratani K, Hayashi H, Shimizu S, Shuta T, Niwa T, et al. Impact of EGFR-TKI treatment on the tumor immune microenvironment in EGFR mutation-positive non-small cell lung cancer. Clin Cancer Res 2020 doi 10.1158/1078-0432.CCR-19-2027. 126. Zaiss DM, van Loosdregt J, Gorlani A, Bekker CP, Grone A, Sibilia M, et al. Amphiregulin enhances regulatory T cell-suppressive function via the epidermal growth factor receptor. Immunity 2013;38(2):275-84 doi 10.1016/j.immuni.2012.09.023. 127. Dayton JS, Lindsten T, Thompson CB, Mitchell BS. Effects of human T lymphocyte activation on inosine monophosphate dehydrogenase expression. J Immunol 1994;152(3):984-91. 128. Feder JN, Guidos CJ, Kusler B, Carswell C, Lewis D, Schimke RT. A cell cycle analysis of growth-related genes expressed during T lymphocyte maturation. J Cell Biol 1990;111(6 Pt 1):2693-701 doi 10.1083/jcb.111.6.2693. 129. Gu JJ, Stegmann S, Gathy K, Murray R, Laliberte J, Ayscue L, et al. Inhibition of T lymphocyte activation in mice heterozygous for loss of the IMPDH II gene. J Clin Invest 2000;106(4):599-606 doi 10.1172/JCI8669. 130. Allison AC, Eugui EM. Inhibitors of de novo purine and pyrimidine synthesis as immunosuppressive drugs. Transplant Proc 1993;25(3 Suppl 2):8-18. 131. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 2005;315(3):971-9 doi 10.1124/jpet.105.084145. 132. Lin A, Giuliano CJ, Sayles NM, Sheltzer JM. CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trials. Elife 2017;6 doi 10.7554/eLife.24179. 133. Fiegle E, Doleschel D, Koletnik S, Rix A, Weiskirchen R, Borkham-Kamphorst E, et al. Dual CTLA-4 and PD-L1 Blockade Inhibits Tumor Growth and Liver Metastasis in a Highly Aggressive Orthotopic Mouse Model of Colon Cancer. Neoplasia 2019;21(9):932-44 doi 10.1016/j.neo.2019.07.006. 134. Antonia S, Goldberg SB, Balmanoukian A, Chaft JE, Sanborn RE, Gupta A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol 2016;17(3):299-308 doi 10.1016/S1470-2045(15)00544-6. 135. Corbett TH, Griswold DP, Jr., Roberts BJ, Peckham JC, Schabel FM, Jr. Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res 1975;35(9):2434-9. 136. Lizotte PH, Hong RL, Luster TA, Cavanaugh ME, Taus LJ, Wang S, et al. A High-Throughput Immune-Oncology Screen Identifies EGFR Inhibitors as Potent Enhancers of Antigen-Specific Cytotoxic T-lymphocyte Tumor Cell Killing. Cancer Immunol Res 2018;6(12):1511-23 doi 10.1158/2326-6066.CIR-18-0193."……… | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/80362 | - |
| dc.description.abstract | 目前臨床試驗結果指出肺腺癌表皮生長因子受體抑制劑(EGFR-TKI)結合免疫檢查點抑制劑(ICB therapy)的合併治療效果不佳，我們推測其中可能的原因之一是表皮生長因子受體抑制劑於治療過程，會干擾免疫檢查點抑制劑作用於胞殺性T淋巴球的作用機制。為了證實此假設，在這篇論文我們募集帶表皮生長因子受體基因突變的肺腺癌患者，透過連續性觀察不同時間點使用表皮生長因子受體抑制劑妥復克(afatinib)治療後，觀察藥物是否會影響胞殺型T淋巴球(CD8+ T lymphocytes)的分化、功能及生長。我們發現短時間藥物處理會抑制胞殺型T淋巴球的生長；然而，長時間的治療過程使胞殺型T淋巴球逐漸適應進而不受藥物干擾抑制，此結果顯示afatinib對於胞殺型T淋巴球，可能存在細微的免疫調節機制。因此，我們透過細胞實驗證明表皮生長因子受體抑制劑妥復克(afatinib)會抑制胞殺型T淋巴球之生長，且同時找到CAD蛋白質為此藥物在T淋巴球中的重要標記蛋白質，此蛋白質在正常生理的角色為調控嘧啶核酸新生成的重要催化酵素。此外，在小鼠皮下植入肺癌細胞並給予afatinib治療，實驗結果顯示胞殺型T淋巴球浸潤至腫瘤組織的數目會因為接受藥物治療而降低。因為有了臨床及細胞實驗結果的佐證，我們更進一步提出階段性給予EGFR-TKI與ICB therapy的概念，透過兩種小鼠腫瘤模式(大腸癌與肺癌)階段性先給予EGFR-TKI標靶治療，再給予免疫治療(ICB therapy)。實驗結果顯示，相較於同時合併治療的效果有限；階段性治療組別，可以較有效降低腫瘤生長與改善有功能性的T淋巴細胞浸潤至腫瘤組織。總結此論文的發現，除了對小分子藥物afatinib如何調節胞殺型T淋巴球的分子機制有更進一步的認識，更進一步提供介入治療時間序的嶄新思維，希望可以避免治療過程表皮生長因子受體抑制劑可能會緩解免疫檢查點抑制劑提升胞殺型T淋巴球的作用。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-24T03:05:10Z (GMT). No. of bitstreams: 1 U0001-1606202116233600.pdf: 5416566 bytes, checksum: d51587aa77a5e3c4b67be74551e8722c (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | "致謝 I 摘要 III Abstract IV List of abbreviations V Introduction 1 Non-small cell lung cancer 1 Immune chckpoint blockade (ICB) therapy 2 ICB therapy in EGFR-mutant NSCLC patients 3 Potential of combined ICB therapy with EGFR-TKIs in NSCLC treatment 4 Identification of on- and off-targets to clinical drug treatment 5 De novo pyrimidine synthesis process 6 Overview of Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) protein 8 Mouse model for lung cancer 9 Research motivation 10 Materials and Methods 11 Patients 11 Animals 11 Cell culture 11 Reagents and antibodies 12 Antibodies and reagents used in flow cytometry analysis 13 Flow cytometry analysis 13 Blood sample collection and processing 14 CFSE proliferation assay 15 Afatinib target protein identification using TISTA, in-gel digestion and LC-MS/MS analysis 15 Western blot 16 Transfection and co-immunoprecipitation 17 Construction of CAD plasmids 18 ADP-Glo ™ Kinase Assay 19 Propidium iodide cell cycle analysis 19 LC/MS-MS metabolomics profiling 20 Isolation of Mouse Tumor-Infiltrating Leukocytes (TILs) 22 Analysis of tumor-infiltrating lymphocytes 23 Immunohistochemistry staining 23 Combination of afatinib treatment and anti-PD1 immunotherapy using MC38- or LLC-bearing mice 24 TCR repertoire sequencing and bioinformatics analysis 25 Statistical analysis 25 Results 26 Afatinib modulated the proliferative capability of CD8+ T lymphocyte in EGFR-mutant NSCLC patients 26 Afatinib suppressed CD8+ T lymphocyte proliferation in human PBMCs and mouse lymphocytes 27 Identification of CAD as one of afatinib interacting-proteins in T cells 28 Characterization of afatinib binding site(s) on CAD proteins 29 Afatinib regulated the de novo pyrimidine synthesis process in T lymphocytes 30 Afatinib induced cell cycle arrest in the G0/G1 phase of cell cycle 31 Role of afatinib on CAD-induced T cell proliferation 32 Afatinib treatment restricted CD8+ TILs penetration into tumor lesions 33 Sequential combination of afatinib with anti-PD1 therapy provides benefits against tumors 34 Potential explanations for CD8+ T lymphocyte rebound in long-term afatinib treatment 35 Discussion 37 References 69" | |
| dc.language.iso | en | |
| dc.subject | 表皮生長因子突變型肺癌 | zh_TW |
| dc.subject | 表皮生長因子受體酪胺酸激酶抑制劑 | zh_TW |
| dc.subject | 嘧啶新生合成 | zh_TW |
| dc.subject | 免疫治療 | zh_TW |
| dc.subject | Immunotherapy | en |
| dc.subject | de novo pyrimidine biosynthesis | en |
| dc.subject | EGFR-mutant NSCLC | en |
| dc.subject | EGFR-TKIs | en |
| dc.title | 第二代表皮生長因子受體抑制劑妥復克透過抑制嘧啶生合成之蛋白質CAD執行免疫調節的作用 | zh_TW |
| dc.title | Second-generation EGFR-TKI afatinib exerts immunomodulatory effects by targeting the pyrimidine biosynthesis enzyme CAD | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 符文美(Hsin-Tsai Liu),顧家綺(Chih-Yang Tseng),張震東,何肇基,莊雅惠 | |
| dc.subject.keyword | 表皮生長因子受體酪胺酸激酶抑制劑,表皮生長因子突變型肺癌,免疫治療,嘧啶新生合成, | zh_TW |
| dc.subject.keyword | EGFR-TKIs,EGFR-mutant NSCLC,Immunotherapy,de novo pyrimidine biosynthesis, | en |
| dc.relation.page | 87 | |
| dc.identifier.doi | 10.6342/NTU202101024 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-06-23 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-1606202116233600.pdf 授權僅限NTU校內IP使用（校園外請利用VPN校外連線服務） | 5.29 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。